Aim 1: Identify genes underlying physiologic water conservation in desert-adapted rodents. Aim 2: Relate fine scale variation in water availability to differential expression of genes identified in Aim 1. The maintenance of water balance in humans is one of the most important physiologic processes. Indeed, humans and most other mammals are exquisitely sensitive to changes in osmolarity, with slight derangement eliciting physiologic compromise. When the loss of water exceeds dietary intake, dehydration occurs. Dehydration is an important source of morality, and can lead secondarily to several common clinical conditions including Acute Kidney Injury (AKI) and End- Stage Renal Failure (ESRD). Unlike most mammals, animals living in desert habitats are subjected to long periods during which no source of extrinsic water is available. As a result, animals living in these environments have evolved mechanisms through which physiologic homeostasis is maintained despite severe and prolonged dehydration. A better understanding of the mechanisms allowing desert-adapted mammals to survive without water intake is directly relevant to human health, with new insights providing fodder for the development of novel strategies aimed at the treatments and prevention of conditions caused by, or associated with, dehydration. Because dehydration can lead to kidney disease, (which affects millions of people (USRDS 2010)), finding effective strategies for its treatment and prevention is urgently needed. Here, I propose to study the genomic underpinnings of functional anuria, an adaptation to the absence of extrinsic water in desert-adapted rodents- using a comparative approach at the intra- and inter-specific levels. Specifically, I will study this phenomenon using three species of rodents within the genus Peromyscus in Southern California. Of these, 2 (P. eremicus and P. crinitus) are desert adapted while a 3rd (P. maniculatus) is a habitat generalist, but is often found in extremely arid non-desert environments. I will sample multiple populations of each species twice- once during the dry season when extrinsic water is unavailable, and once during the rainy reason, when water is maximally available. Samples (mRNA molecules) will be subjected to whole genome profiling (Illumina sequencing) and gene expression will be compared between seasons. I will compare gene expression in dry versus wet seasons in all species. Genes that are differentially expressed in the dry season are likely to be related to water conservation. Within the set of genes that are differentially expressed in the dry season, those that are specific to desert-adapted species are likely critical for persistence in desert environments (e.g., likely underlie anuria). PUBLIC HEALTH RELEVANCE: The research described in this proposal will reveal the genomic underpinnings of physiologic water conservation (e.g. anuria), an adaptation to the absence of extrinsic water, in desert- adapted rodents. A better understanding of the mechanisms allowing desert-adapted mammals to survive without water intake is directly relevant to human health, with new insights providing fodder for novel strategies aimed at the treatments and prevention of conditions caused by, or associated with, dehydration. Because these conditions affect millions of people, finding effective strategies for its treatment and prevention is urgently needed.